Changes in blood oxygen affinity, spontaneous or induced, may critically affect oxygen transport to cells. We therefore propose (a) to define circumstances in which and the degree to which increased oxygen affinity impairs function of various organs; and (b) to determine whether decreased oxygen affinity may impair cellular function when oxygen supply is compromised. Three specific objectives and two secondary ones are proposed. (1) We propose to determine the effect of increased and decreased P50 in rats using a combined exchange transfusion - hemorrhagic shock model with which we have considerable experience and promising pilot experiments. Parameters to be examined include duration of ability to tolerate shock, ultimate survival, oxygen consumption, arterial blood gases, acid-base balance and arterial lactate. (2) We propose to examine the effect of decreased and increased P50 on muscle oxygen consumption during rest and work in a perfused sciatic nerve- gastrocnemius preparation. Following exchange transfusion we will measure oxygen consumption as a function of P50 at a variety of blood flow rates and levels of work induced by nerve stimulation. (3) Experiments in progress show a marked effect of decreased P50 on performance capacity in exercising rats, probably due to an effect on skeletal muscle or on the heart. We propose to clarify the mechanism by studying heart rate, arterial lactate and arterial and venous PO2, PCO2 and pH at various levels of exercise in animals with decreased P50 and in normal and anemic controls. Secondary objectives entail (4) assessment of red-cell mass adjustments on maximal oxygen consumption and hemodynamics in human subjects with congenitally altered oxygen affinity and (5) development of a computer model describing oxygen delivery and CO2 exchange at the tissue level, the latter being used to clarify and interpret experimental results and suggest other experiments.